No proven treatments exist to prevent the radiation-induced skin reactions that are experienced by 95% of cancer patients receiving radiation therapy. Current standard care for radiation dermatitis involves topical products that are prescribed once radiation-induced skin reactions occur, despite the lack of evidence to support the benefit of any such treatments. Although research suggests that topical agents with anti-inflammatory and moisturizing properties may prevent and/or reduce radiation-induced skin reactions, few studies have tested and/or compared the prophylactic effects of topical treatments. For example, both preclinical and clinical studies have shown that increased transepidermal water loss (TEWL) correlates with increased severity of radiation dermatitis. We hypothesize that moisturizing topical interventions with anti-inflammatory properties could reduce radiation dermatitis severity by minimizing TEWL and inflammation during radiation therapy. We propose to conduct a randomized, three-armed, placebo-controlled, blinded clinical pilot trial (N=150) to compare the prophylactic effects of two investigational topical agents, MimyX(R) (0.3% PEA) and Curcumin (4%) gel, versus placebo gel added to the University of Rochester Cancer Center standard care on the severity of radiation dermatitis and associated pain. The innovative design of this clinical trial will provide results that show either current standard care is the best treatment option or that prophylactic use of another topical intervention is the best option., Additionally, results will determine if a preventive approach (i.e., before onset of skin reaction) to clinical care of radiation dermatitis is superior to a treatment approach (i.e., after onset of skin reaction). This research proposal incorporates a unique, multidisciplinary team with expertise in the fields of dermatology, radiation oncology, and cancer control. Ultimately, the goal of this study is to identify one or two topical agents for further evaluation in a phase II/III efficacy trial for preventing and/or reducing RT-induced skin reactions and associated pain. Findings from this trial could advance the approach to clinical management of radiation dermatitis, an extremely common toxicity encountered by the majority of patients receiving radiation therapy for cancer.